Sampling of starting and packaging materials: Glycerol as per EU GMP
EU GMP guide annexes: Supplementary requirements: Annex 8: Sampling of starting and packaging materials: Glycerol
1. What is the background regarding international incidents of glycerol contamination? H+V December 2007
There is a history of sporadic reports from around the world of supplies of glycerol contaminated with diethylene glycol (DEG) resulting in mortality and serious morbidity in patients receiving contaminated products.
In late 2006, DEG-contaminated glycerol in cough syrup was the cause of about 50 deaths in Panama.
DEG-contaminated glycerol in paracetamol syrup was also attributed to at least 80 deaths in a similar incident in Haiti in 1995-1996.
Other incidents have been reported in Argentina, Bangladesh, India and Nigeria and attributed to the deaths of hundreds of children. DEG was also responsible for a poisoning incident resulting in the death of 107 people in the United States in 1937, following ingestion of contaminated sulphanilamide elixir.
These incidents were related to both accidental cross-contamination of glycerol with industrial grade materials and, in some cases, to intentional substitution.
Recent cases show the following similarities:
Pharmaceutical manufacturers of products containing contaminated glycerol did not perform full identity testing or tests to determine DEG on the glycerol raw material;
Pharmaceutical manufacturers of contaminated products relied on certificates of analysis (COAs) provided by the supplier;
The origin of glycerine was not apparent from the COA. The COA provided with the glycerol raw material may have been a copy of the original on a distributor letterhead. The supply chain for glycerol was not readily known by the medicinal-product manufacturer because the glycerol may have been sold several times between its manufacture and the medicinal product manufacturer.
2. How is the EU patient protected from similar contamination occurring in EU products? H+V December 2007
EU GMP requires all manufacturing companies to confirm that all its raw materials are checked on receipt to confirm their identity and quality. Competent authorities expect product manufacturers to routinely ensure that incoming samples of glycerol are tested according to the European Pharmacopoeia monograph.
The European Pharmacopoeia monograph for glycerol includes a specific limit test for diethylene glycol (0.1%).
3. Annex 8 of the GMP provides for derogations from the requirement for identity testing of every
container where there is a validated supply chain. Can I use this derogation for the glycerol I
purchase? H+V December 2007
It is correct that annex 8 does provide for a relaxation of identity testing of every container, but it also states that this would not normally be possible if brokers or intermediates were involved in the chain of supply.
Glycerol is a commercial article that is widely used in the food and other industries. Generally speaking, the supply chain for glycerol tends to be complex and lengthy. The involvement of brokers is common in the supply chain.
4. What steps are expected of manufacturers based in the EU when purchasing glycerol or of
manufacturers based in third countries supplying glycerol-containing medicines? H+V December 2007
When designing supplier-assurance and incoming-goods-control programmes, companies should consider glycerol a higher-risk material.
Companies should be able to exhibit a good knowledge of starting material supply chains and apply this knowledge and principles of quality risk management to their programmes for supply-chain management.
Inspectors will look to ensure that the basis for qualification of the supply chain is demonstrably robust for higher-risk materials such as glycerol. It is expected that identity testing and the European Pharmacopoeia limit test for DEG will be performed on each container as a matter of routine.
5. The European Pharmacopoeia limit test for DEG involves a gas chromatographic method, which
may be difficult to perform on a large number of containers. H+V December 2007
This point is acknowledged and currently, alternative tests are under consideration with a view to work up a possible change to the identity tests in the monograph. The European Pharmacopoeia DEG limit test remains the official method for confirmation of compliance with the monograph.
6. Are there any considerations applicable to the pharmaceutical assessment of marketing authorisation applications? H+V July 2008
In application dossiers for new marketing authorisations (MAs), or in case of relevant variations for existing MAs (for example, replacement of an excipient with glycerol) for medicinal products containing glycerol, confirmation of the tests applied on receipt of batches of glycerol to control the risk from potential DEG contamination in relation to the specific intended use of the product should be provided.
A test for DEG content should be conducted in addition to identity testing for glycerol. A suitable control for DEG is included in the European Pharmacopoeia monograph for glycerol.
Sufficient information regarding satisfactory control of this risk will be required in the dossier before
approval of the MA application or variation.
For existing approved medicinal products, no variation application is required, except for those few specific types of variations referred to in the first paragraph. However, as a minimum, the specific European Pharmacopoeia control for DEG should be conducted along with the identity test at receipt of each batch of glycerol.
The excipient is required to comply with the current European Pharmacopoeia glycerol monograph, and as the specification approved in the dossier will have been that of the European Pharmacopoeia, the risk of DEG contamination will have been appropriately controlled. Compliance with this requirement will be verified during GMP inspections.
7. My company manufactures products for external use. Does this guidance apply? H+V July 2008
Where a company manufactures products for external use, and when it has justified that the presence of DEG in these products poses a low risk, the omission of the test for DEG on each container may be accepted by the supervisory authority.